Fatty acid amide hydrolase (FAAH) knockout mice exhibit enhanced acquisition of an aversive, but not of an appetitive, Barnes maze task

It is well established that genetic deletion or pharmacological inhibition of the CB₁ receptor disrupts extinction learning in aversive conditioning tasks, but not in appetitive tasks. Consistent with these findings is that genetic deletion or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endogenous cannabinoid anandamide (AEA), accelerates acquisition as well as extinction in aversive conditioning tasks. However, it is unknown whether FAAH blockade will affect acquisition in an appetitive conditioning task. Therefore, in the present study, we assessed FAAH (−/−) and (+/+) mice in appetitive and aversive Barnes maze conditioning procedures. Here we report that FAAH (−/−) mice displayed accelerated acquisition rates in an aversively-motivated, but not in the appetitively-motivated, Barnes maze task. The CB₁ receptor antagonist, rimonabant attenuated enhanced acquisition in the aversive procedure, consistent with the idea that elevated AEA levels mediate this apparent nootropic effect. These findings support the hypothesis that stimulation of the endocannabinoid system enhances learned behavior in aversive, but not appetitive, conditioning paradigms.     

前额皮层肾上腺素能受体在工作记忆中的作用

前额皮层去甲肾上腺素能神经支配主要来自脑干蓝斑核。前额皮层存在不同类型的肾上腺素能受体。其中突触后α2及β2肾上腺素能受体的激活提高工作记忆;α1及β1肾上腺素能受体的激活损害工作记忆。不同受体是通过激活不同的信号通路发挥对工作记忆的调节作用。来自人类被试的研究结果与对动物的研究结果之间尚存在不一致。了解前额皮层不同肾上腺素受体的作用为开发治疗与前额皮层功能失调相关疾病的药物提供了新的方向。     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decresed, progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and, female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress induced behavioral depression.     

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

The dentate gyrus (DG) is among the few areas in the mammalian brain where production of new neurons continues in the adulthood. Although its functional significance is not completely understood, several lines of evidence suggest the role of DG neurogenesis in learning and memory. Considering that long-term potentiation (LTP) is a prime candidate for the process underlying hippocampal learning and memory, these results raise the possibility that LTP and neurogenesis are closely related. Here, we investigated whether or not LTP induction in the afferent pathway triggers enhanced proliferation of progenitor cells in the DG. LTP was induced by tetanic stimulation in perforant path-DG synapses in one hemisphere, and the number of newly generated progenitor (BrdU-labeled) cells in the DG was quantified. Compared with the control hemisphere (stimulated with low-frequency pulses), the LTP-induced hemisphere contained a significantly higher number of newly generated progenitor cells in the dorsal as well as ventral DG. When CPP, an NMDA receptor antagonist, was administered, tetanic stimulation neither induced LTP nor enhanced progenitor cell proliferation, indicating that NMDA receptor activation, rather than tetanic stimulation per se, is responsible for enhanced progenitor proliferation in the control animal. Our results show that tetanic stimulation of perforant path sufficient to induce LTP increases progenitor proliferation in adult DG in an NMDA receptor-dependent manner.     

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

The present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1 mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1 mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5 mg/kg) and MK-801 (0.05 mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1 mg/kg and 0.1 mg/kg, respectively) or concomitantly at sub-effective doses (0.5 mg/kg and 0.05 mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands.     

海马NMDA受体经SP-NK1受体通路参与慢性应激诱发的抑郁样行为

为探讨海马N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体与P物质(Substance P, SP)及其神经激肽1 (neurokinin1, NK1)受体在慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS) 中的作用及其关系, 通过建立CUMS动物模型, 大鼠海马微量注射给药, 测量大鼠体重, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用高效液相色谱(HPLC)法分析大鼠海马组织中SP和谷氨酸(glutamate, Glu)的含量变化。结果显示, CUMS诱发大鼠表现出明显的抑郁样行为, 海马组织中SP和Glu水平显著增加; 海马注射NMDA, 大鼠表现出与CUMS/SAL组相似的抑郁样行为, 且海马组织中SP的含量比正常对照组显著增加; 微量注射NK1受体阻断剂CP-96345和/或NMDA受体阻断剂MK-801后, 大鼠抑郁样行为明显改善, 且MK-801使CUMS导致的大鼠海马P物质水平升高得到明显控制, 而CP-96345没有明显改变CUMS引起的海马Glu水平升高; CP-96345使NMDA引起的抑郁样行为得到极显著改善。以上结果表明, 慢性应激引起大鼠海马Glu过量释放, 通过激活NMDA受体, 促进P物质合成释放增加, 激活NK1受体, 是导致抑郁样行为发生的重要途径之一。     

Depression in early adolescence: Contributions from relational aggression and variation in the oxytocin receptor gene

Interpersonal stress arising from relational aggression (RA)—the intentional effort to harm others via rejection and exclusion—may increase risk for depression in youth. Biological vulnerabilities related to the hormone oxytocin, which affects social behavior and stress responses, may exacerbate this risk. In a community sample of 307 youth (52% female; age range = 10–14 years), we tested whether (1) the association between RA and subsequent depressive symptoms was mediated through social problems and (2) a single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) moderated this indirect association between RA and depression, where GG homozygotes are predicted to be more sensitive to the effects of social problems than A‐allele carriers. Youth‐reported RA and depressive symptoms were measured using a structured interview and a questionnaire, respectively. DNA was extracted from saliva collected with Oragene kits. Consistent with the interpersonal theory of depression, the association between relational aggression and subsequent depressive symptoms was mediated by social problems. This indirect effect was further moderated by rs53576 genotype, such that GG homozygotes showed a stronger mediation effect than A‐carriers. These results suggest that rs53576 variants confer vulnerability for depression within the context of interpersonal risk factors, such that youth with the GG genotype may be particularly sensitive to the social consequences resulting from RA.

     

Effect of the 5-HTTLPR polymorphism on posttraumatic stress disorder,depression, anxiety,and quality of life among Iraq and Afghanistan veterans

Background and Objectives: Posttraumatic stress disorder (PTSD), depression, anxiety, and stress are significant problems among returning veterans and are associated with reduced quality of life. Design: A correlational design was used to examine the impact of a polymorphism (5-HTTLPR) in the serotonin transporter promoter gene on post-deployment adjustment among returning veterans. Methods: A total of 186 returning Iraq and Afghanistan veterans were genotyped for the 5-HTTLPR polymorphism. Symptoms of PTSD, depression, general stress, and anxiety were assessed along with quality of life. Results: After controlling for combat exposure, age, sex of the participant, and race, 5-HTTLPR had a significant multivariate effect on post-deployment adjustment, such that S′ carriers reported more post-deployment adjustment problems and worse quality of life than veterans homozygous for the L′ allele. This effect was larger when the analyses were restricted to veterans of European ancestry. Conclusions: Our findings suggest that veterans who carry the S′ allele of the 5-HTTLPR polymorphism may be at increased risk for adjustment problems and reduced quality of life following deployments to war zones.